This invention relates to a method of protecting living tissue from damage caused by hypoxic or ischemic conditions such as those resulting from acute vascular occlusions. More particularly, the present invention relates to the use of synthetic oxygen carriers, including perfluorocarbon-based emulsions, to carry gases to hypoxic or ischemic living tissue, and thereby ameliorate damage.
Normal animal physiology requires efficient delivery of oxygen to living cells and tissues and efficient removal of carbon dioxide and other waste products of metabolism. In mammals, this is generally accomplished by gas exchange mediated by hemoglobin-containing red blood cells, and is primarily accomplished by red blood cells flowing through capillaries. When capillaries or larger arteries become occluded, such as by vessel constriction or solid emboli that block or partially block the blood vessels, the oxygen supply becomes compromised for tissues that depend on those vessels for oxygen. Tissue hypoxia results from failure to transport sufficient oxygen, often due to inadequate blood flow i.e. ischemia. Hypoxia can result from internal hemorrhage (e.g., intracerebral hemorrhage producing cerebral hypoxia), anemia or trauma. Ischemia is a deficiency of blood supply to the tissue due to functional constriction or actual obstruction of a blood vessel. For example, myocardial ischemia is a deficiency of blood supply to heart muscle due to obstruction or constriction of the coronary arteries. If ischemia continues for more than a few seconds, tissue damage can result from a complex series of biochemical events associated with the ischemia-induced tissue hypoxia.
Hypoxic or ischemic conditions produced by emboli can result in tissue damage that is particularly debilitating if the damaged tissue is heart tissue or neural tissue of the central nervous system (CNS). The two most serious consequences of emboli are heart attack (acute myocardial infarct or AMI), resulting from cardiac muscle ischemia, and stroke, resulting from brain tissue ischemia. Ischemia which does not lead to AMI or stroke can, nonetheless, produce serious symptoms in the individual such as chest pains (angina pectoris), partial paralysis, confusion, disorientation and/or memory loss.
Individuals with vascular disease, particularly atherosclerosis, are particularly at risk for developing emboli that can result in AMI or stroke. Ischemic heart disease affects millions of people worldwide, often leading to sudden death by AMI. Ischemia can result when solid emboli produced from portions of plaque that dislodge and move through the circulatory system lodge in a capillary or attach to another plaque deposit in a blood vessel, thus fully or partially occluding the vessel or capillary. Atheromatous plaque particles can also be generated during vascular and cardiac surgery procedures (e.g. cannulation, clamping) that manipulate or disturb any atherosclerotic blood vessels (e.g., carotids, coronaries, aorta, femoral or popliteal vessels).
Present day treatment of occlusions generally involves bypassing the blocked vessel, or removing and/or dissolving emboli using mechanical means and/or thrombolytic enzymes. For example, treatment of intracoronary thrombotic events such as myocardial infarcts usually involves one or a combination of treatments. These include coronary bypass surgery, percutaneous coronary angioplasty (PTCA) and systemic administration of thrombolytic agents, such as tissue plasminogen activator (tPA) or streptokinase. Although such treatments often successfully relieve the hypoxic or ischemic condition, significant damage to the tissue in the hypoxic zone can occur before treatment is completed.
Synthetic oxygen carriers, often referred to as xe2x80x9cblood substitutesxe2x80x9d have been shown to augment delivery of oxygen through the circulatory system when red blood cells (i.e., hemoglobin) are partially depleted, such as during surgery, or resulting from injury with bleeding or hemorrhagic disorders. Similarly, synthetic oxygen carriers can be used to treat conditions where the red blood cells are partially non-functional, as may occur in patients with certain genetic disorders, or patients undergoing hypothermic procedures such as cardiopulmonary bypass or circulatory arrest. Such oxygen carriers or blood substitutes are disclosed in U.S. Pat. No. 5,344,393 and U.S. Pat. No. 5,451,205. Other blood substitutes are known as disclosed in U.S. Pat. No. 5,114,932, U.S. Pat. No. 4,423,077, U.S. Pat. No. 4,397,870, U.S. Pat. No. 4,186,253, U.S. Pat. No. 4,173,654, U.S. Pat. No. 4,423,077, U.S. Pat. No. 3,962,439 and U.S. Pat. No. 3,937,821. Perfluorocarbon emulsions, such as FLUOSOL(trademark) (Green Cross Corporation, Japan) and OXYGENT(trademark) (perflubron-based emulsion) (Alliance Pharmaceutical Corp., San Diego, USA), are known to be efficient synthetic oxygen carriers that are generally well tolerated in vivo by humans. Synthetic oxygen carriers comprising hemoglobin, which can be derived from human, animal, or recombinant sources, is also known in the art
Given the excellent oxygen dissolving characteristics and biocompatibility of perfluorochemicals, previous efforts have led to their use in neurologic ischemia. For example, one system includes perfluorocarbon in a nutrient emulsion or xe2x80x9csynthetic cerebrospinal fluidxe2x80x9d to treat CNS hypoxic-ischemic conditions (U.S. Pat. No. 4,445,514). In this case the oxygenated emulsion is administered directly into the cerebrospinal fluid and artificially circulated through extracorporeal means.
Perfluorocarbon emulsions have also been used in an experimental animal model of partial brain stem ischemia and shown to enhance recovery of brain stem function following reperfusion (Guo et al., Neurosurgery 36(2): 350-357, 1995).
Perfluorocarbons and blood substitutes have also been used for drug delivery. For example, infusions of a neuroprotectant and a perfluorochemical emulsion have been disclosed as a treatment for conditions involving cerebral hypoxia (PCT International Application No. WO 97/15306).
According to the invention, there is provided a method of preventing or treating tissue hypoxia or ischemia, including the step of administering systemically a synthetic oxygen carrier to an individual having or suspected of having blood vessel obstruction. Preferably, the invention may be used to provide neuroprotection or retard neurodegeneration in a patient in need thereof through a reduction in the adverse effects of cerebral ischemic hypoxia. Other preferred embodiments comprise the use of synthetic oxygen carriers in chronic or long-term therapeutic regimens for the reduction or treatment of ischemic or hypoxic associated effects. Another embodiment comprises the use of perfluorochemical-based formulations to reduce the inflammatory process triggered locally by the ischemic insult and related tissue hypoxia. In selected embodiments, the oxygen carrier is administered by intravenous injection or infusion. Preferably, the synthetic oxygen carrier is a perfluarocarbon emulsion, crystalloid blood substitute, a colloid blood substitute, or combinations thereof.
As such, in a broad sense the present invention comprises the use of a synthetic oxygen carrier in the manufacture of an oxygen carrying medicament for the treatment of tissue hypoxia due to ischemia or acute anemia, wherein said oxygen carrying medicament is administered systemically to an individual having or suspected of having blood vessel obstruction caused by solid emboli, or temporary clamping of vessels during surgery.
Particularly preferred embodiments of the invention comprise the use of synthetic oxygen carriers which are fluorocarbon-in-water emulsions comprising a discontinuous fluorocarbon phase and a continuous aqueous phase. In another embodiment, the fluorocarbon-in-water emulsion includes a perfluorocarbon phase and an aqueous phase. In another embodiment, the fluorocarbon emulsion also includes an emulsifying agent or dispersant, osmotic agent, buffer, electrolyte or combinations thereof.
Generally it will be appreciated that the term xe2x80x9cfluorocarbonxe2x80x9d is used in a broad sense and comprises any highly fluorinated compound such as a linear, branched, cyclic, saturated or unsaturated fluorinated hydrocarbon, optionally containing at least one heteroatom and/or bromine or chlorine atom, wherein at least 30% of the hydrogen atoms of said hydrocarbon compound have been replaced by fluorine atoms. Particularly preferred embodiments comprise perfluorocarbons. Other embodiments comprise fluorocarbon emulsions including bis(F-alkyl) ethanes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, chlorinated fluorocarbons, perfluoroalkylated ethers, perfluoroalkylated polyethers or mixtures thereof that are dispersed in an aqueous phase. Fluorocarbons compatible with the present invention are generally selected for beneficial physical characteristics such as low toxicity, low surface tension, high spreading coefficient and the ability to transport gases.
Hemoglobin compositions contemplated for use in the present invention are well known. These compositions may be comprised of stroma-free, intramolecularly cross-linked, conjugated, polymerized, or recombinant hemoglobin or combinations thereof. Such compositions are disclosed, for example, in the following U.S. Patents, which are hereby incorporated by reference: U.S. Pat. Nos. 4,911,929; 4,861,867; 4,857,636; 4,777,244; 4,698,387; 4,600,531; 4,526,715; 4,473,494; and 4,301,144.
In yet another aspect, the present invention provides methods for delivering a bioactive agent to a patient using the disclosed oxygen carriers. As used herein, the term bioactive agent is defined to mean any pharmaceutical compound or composition, including diagnostic and therapeutic agents or drugs as well as physiologically acceptable gases such as oxygen or nitric oxide, which may be administered to an animal to treat a disorder or disease. Specific bioactive agents or drugs compatible with the present invention include, but are not limited to, antibiotics, antivirals, anti-inflammatories, antineoplastics, intravenous anesthetics, volatile anesthetics, enzymes, cardiovascular agents, polynucleotides, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins and combinations thereof. Preferably, the incorporated drug is a drug that promotes dissolving emboli, or a neuroprotective compound. In a selected embodiment, the neuroprotective compound is a neuropeptide, a nerve growth factor or 2-aminobenzothiazole derivative.
Accordingly, in preferred embodiments the invention provides for the use of a synthetic oxygen carrier in the manufacture of an oxygen carrying medicament for providing neuroprotection or retarding neurodegeneration through a reduction in effects associated with cerebral ischemia or hypoxia wherein said oxygen carrying medicament is administered systemically to a patient in need thereof.
More broadly, the present invention provides for the delivery of bioactive agents using emulsified medicaments capable of carrying oxygen. That is, embodiments of the present invention comprise the use of a fluorocarbon in the manufacture of an oxygen carrying emulsified medicament for the delivery of a bioactive agent wherein said emulsified medicament comprises an aqueous continuous phase, a nonaqueous dispersed phase, an emulsifying agent and a bioactive agent and wherein said emulsified medicament is administered to a patient in need thereof.
Consistent with the teachings herein the oxygen carrier may be administered either prophylactically to prevent the ischemia-induced tissue hypoxia, or as a treatment of therapy for symptoms associated with ischemia, whereas in other embodiments the administration step is performed after the ischemic event to correct symptoms associated with ischemia or hypoxia. The administration step may be performed prior to a surgical procedure to protect against emboli which will cause ischemia, or during the surgical procedure, or within 24 hours or several days after a surgical procedure to treat tissues at risk of hypoxia to emboli or other ischemic events.
As indicated above, other embodiments of the invention comprise the chronic or long term administration of oxygen carriers to reduce the deleterious effects of ischemic or hypoxia. Such therapeutic regimens may involve the low dose administration of the selected oxygen carrier for a period of weeks or even months. The actual administration of the oxygen carrier may preferably comprise discrete introductions on a periodic basis (i.e. once a day or once a week) or a constant slow infusion of the oxygen carrier using techniques well known in the art. In these embodiments, the oxygen carrier may further comprise an additional bioactive agent. It will be appreciated that such regimens may be particularly useful for ameliorating symptoms associated with chronic neurodegenerative conditions such as Alzheimer""s disease, Parkinson""s disease or epilepsy. Of course, it will further be appreciated that the long term administration of oxygen carriers may be used to treat non-neuronal conditions.
Accordingly, preferred embodiments of the invention provide for use of a synthetic oxygen carrier in the manufacture of an oxygen carrying medicament for the treatment of a chronic or long term hypoxic or ischemic condition in a patient in need thereof wherein said oxygen carrying medicament is administered periodically, intermittently or continuously to said patient for a treatment period greater than one week.
In another embodiment, the method includes administering a volume of an intravenous fluid including the synthetic oxygen carrier, wherein the synthetic oxygen carrier is at least about equal to 0.1% of the individual""s normal blood volume. In other embodiments, the volume of an intravenous fluid including the synthetic oxygen carrier is equal to about 1% to about 20%, or 30% of the individual""s normal blood volume.
According to another aspect of the invention, there is provided a composition including a synthetic oxygen carrier in a physiologically acceptable carrier, wherein the synthetic oxygen carrier includes submicron-sized particles capable of passing through emboli-obstructed blood vessels. In one embodiment, the synthetic oxygen carrier is a fluorocarbon-in-water emulsion of a discontinuous fluorocarbon phase and a continuous aqueous phase, wherein the fluorocarbon phase includes submicron sized particles. In another embodiment, the fluorocarbon-in-water emulsion also includes an emulsifying agent, osmotic agent, buffer, electrolyte, therapeutic drug or combinations thereof. Particularly preferred compositions of the present invention comprise fluorochemical emulsions that further incorporate at least one neuroprotective bioactive agent. Additional embodiments include oxygen carriers derived from human, animal, plant, or recombinant hemoglobin.
That is, the present invention further provides compositions comprising a synthetic oxygen carrier in a physiologically acceptable carrier, wherein the synthetic oxygen carrier comprises submicron sized particles capable of passing through emboli-obstructed blood vessels.